Indomethacin compositions



3,461,208 INDOMETHACIN COMPOSITIONS Charles A. Winter, Blue Bell, Pa.,assignor to Merck & Co., Inc., Rahway, N.J., a corporation of New JerseyN Drawing. Continuation-impart of application Ser. No. 328,578, Dec. 6,1963, which is a continuation-in-part of application Ser. No. 131,093,Aug. 14, 1961. This application Nov. 1, 1966, Ser. No. 591,113.

Int. Cl. A61k 17/16, 27/00 US. Cl. 424-243 2 Claims ABSTRACT OF THEDISCLOSURE Dexamethasone (or a like anti-inflammatory adrenocorticalsteroid is combined with indomethacin (or a like anti-inflammatoryindole) in a single pharmaceutical dosage form to make it possible toadminister a smaller amount of the steroid.

This application is a continuation-in-part of Ser. No. 328,578, filedDec. 6, 1963, now abandoned, which in turn is a continuation-in-part ofSer. No. 131,093, filed Aug. 14, 1961, now abandoned.

Mg. Cortisone 4-25 Hydrocortisone 4-20 Prednisone 0.75-5 Prednisolone0.755 Methylprednisolone 0'.754 Fluprednisolone 030- Triamcinalone 0.754

Dexamethasone 0.1250.75 Betamethasone 0.1'0-016 Paramethasone 0.40-2

All of these corticosteroids cause undesirable side effects whenadministered in a therapeutic dose over extended periods of time. Forexample, they variously cause a moonfaced appearance, osteoporosispeptic ulcer complications, and adrenocortical insufliciency. For thisreason it is the usual practice to administer them in the lowestpossible doses compatible with the desired effect and any method ofachieving their potent beneficial results without these side eflects isa great advance in the therapy of inflammation.

The present invention achieves this reduction in corticosteroid bycombining with it indomethacin or closely chemically related indolecompounds. Indomethacin is sold under the trademark Indocin (Merck) anda unit dose of it in the present invention is from 5 to 25 mg.

nited States Patent O 3,461,208 Patented Aug. 12, 1969 Its preferredchemical name is 1(p-chlorobenzoyl)-5- methoxy-2-methyl-indole-3-aceticacid and it can be named as l-p-chlorobenzoyl 2methyl-5-methoxy-3-indolyl-acetic acid. Other chemically andphysiologically related compounds are:

1- (p-chlorob enzylidene) -5-methoxy-2-methylindene acetic acid, 5-25mg.

1- p-chlorobenzoyl) -5-dimethylamino-Z-methylindole acetic acid, 1050mg.

a-l-(p-methylmercaptobenzoyl)-5-methoxy-2-methylindole propionic acid,10-50 mg.

a- 1 (p-ehlorobenzoyl) -5 -methoxy-2-methylindole propionic acid, 15-75mg.

a-l-(p-methylmercaptobenzyl)-5-methoxy-2-methylindole propionic acid;also named as: a-( l-p-methylthiobenzyl-Z-methyl 5 methoxy-S-indolyl)propionic acid, 75-100 mg.

a-l-(p-chlorobenzyl)-5-methoxy-2-methylindole propionic acid, 40-200 mg.

The esters and/ or salts of the above steroids or indole compounds maybe used as well.

These indole compounds, like the steroids, exhibit a high degree ofanti-inflammatory activity and are themselves useful for the treatmentof arthritic and related conditions. However, because they too arepotent substances, it is desirable to use the lowest dose possible toobtain the desired beneficial therapeutic effect.

In accordance with the present invention it has been found that acombination of one of the above-mentioned corticosteroids and one of theabove-mentioned indole compounds produces a synergistic degree ofanti-inflammation, activity, thereby making it possible to lower thedose level so that the undesirable side effects are minimined. In severeinflammatory conditions, the higher amounts of the selected steroid andthe selected indole may be combined with beneficial results as a greateranti-inflammatory response will be obtained than can be achieved witheither drug alone even if an extremely large dose is given. A physicianmay prefer such high doses, despite the adverse side eiiects, to give apatient adequate relief from pain. In describing the action of thesemixtures or combinations as synergistic, I therefore mean either thatthe combined activity of the two components is greater than the sum ofthe activities when the components are used alone, or that the use ofthe combination permits the achievement of the same therapy with dosesof steroids greatly reduced over those needed when the steroid is usedalone.

The novel compositions of this invention comprise pharmaceuticalpreparations suited for oral, topical or parenteral administration andthey are prepared by techniques and skills known in the pharmaceuticalart. They include tablets or capsules for oral administration, where theactive ingredients are mixed with binders, fillers and excipients suchas starch, glucose or lactose, and syrups or elixirs where theanti-inflammatory agents are dissolved or suspended in a suitable liquidvehicle. For topical use, creams, ointments, jellies, solutions orsuspensions containing the anti-inflammatory agents are employed, andfor parenteral, intra-muscular or intra-articular administration,sterile solutions or suspensions are used.

In making up the compositions of the invention, one of thecorticosteroids within the range given above would 3 be combined withthe selected indole within the stated range. This unit dosage form wouldbe taken one to four times daily at spaced time intervals, as indicatedby the need of the particular patient.

This invention is illustrated by the following examples:

The prednisolone, sodium u-(l-p-methylthiobenzyl-Z-methyl--methoxy-3-indoyl)-propionate, lactose and corn starch arereduced to a fine powder by milling and remixing. The mixture isgranulated with the cellulose acetate phthalate solution. The wettedmass is passed through a No. stainless steel screen and dried in thedark at 110 F. The dried granules are passed through a No. 20 stainlesssteel screen, and the additional quantity of corn starch, guar gum andmagnesium stearate added. The mixture is compressed using a standardcurvature punch into tablets and the tablet may be coated with aconventional protective film.

The hydrocortisone, indolyl propionate, calcium phosphate and lactoseare mixed to a fine powder, i.e. through 60 mesh. The powder isgranulated with the ethyl cellulose solution and the moist mass passedthrough a No. 10 screen, dried at 110 F. and rescreened through a No. 20stainless steel screen. The corn starch and magnesium stearate are addedand the mixture compressed to tablets with an punch. These tablets maybe coated with a protective film.

EXAMPLE 3 Per tablet, mg. Hydrocortisone 8.0 1 p chlorobenzoyl 2 methyl5 methoxy 3- indolyl-acetic acid 10.00 Lactose 87.17 Starch, corn 5.00Cellulose acetate phthalate (2% in acetone 2.00

Add:

Starch, corn 5.00 Guar gum 5.00 Magnesium stearate 2.00

The tablets are prepared as described in Example 1.

4 EXAMPLE 4 Per tablet, mg. Dexamethasone 0.125 Sodium a (1 pmethylthiobenzyl 2 methyl-5-methoxy-3-indolyl)-propionate 7.50000Calcium phosphate, dibasic 80.0000 Magnesium stearate 1.0000

Add:

Starch, corn 5.0000 Magnesium stearate 1.0000

The tablets are prepared as described in Example 1.

EXAMPLE 5 Per tablet, mg. Dexamethasone 0.125 1 (p chlorobenzoyl) 5methoxy 2 methylindole-3-acetic acid 25.0 Calcium phosphate, dibasic80.0 Magnesium stearate 1.0

Add:

Corn starch 5.0 Magnesium stearate 1.0

The tablets are prepared as in Example 1.

EXAMPLE 6 Example 5 is followed except that twice as much dexamethasone,namely 0.250 mg, is used.

EXAMPLE 7 Examples of capsules containing the steroid and nonsteroidanti-inflammatory agent follow:

Per tablet, mg.

Dexamethasone 0.250 Sodium a (1 p methylthiobenzyl 2methyl-5-methoxy-3-indolyl)-propionate 7.5000

Lactose 420.4775

Lactose 415.25 Magnesium stearate 2.00

The mixed powder is encapsulated.

EXAMPLE 9 Per capsule, mg. Hydrocortisone 10.0

1 p chlorobenzoyl 2 methyl 5 methoxy 3- indolyl-acetic acid 25.00

Lactose 250.00 Magnesium stearate 1.00

The powdered components are mixed and put into a No. 3 opaque gelatincapsule.

EXAMPLE 10 In Example 9, instead of hydrocortisone, there is used 0.125mg. of dexamethasone.

EXAMPLE 11 The following represents examples of sterile aqueoussuspensions of the therapeutic mixtures described above:

Per ml., mg. Prednisolone 1.125

Sodium a (1 p methylthiobenzyl 2 methyl- 5-methoxy-3-inodlyl)-propionate7.500 Glyceryl monostearate 10.000 Polysorbate 0.050 Sodium chloride0.500 Methyl parahydroxybenzoate 0.150 Pyrogen-free water to make 1.000

6 The glyceryl monostearate and Polysorbate 80 are disvehicle.Suflicient additional water is then added to give persed at 65 C. inwater containing the sodium chloride the desired volume and it is putinto vials. and methyl paraphydroxybenzoate. The resulting mixturePatients suffering from various allergic and/or inflamis sterilized byautoclaving. After the vehicle has cooled matory diseases and conditionswho had previously been to room temperature sterile microcrystallineprednisolone on steroid therapy were put on therapy using mixtures andsodium e-(1-p methylthiobenzyl-Z-methyl-S-methoxy- 5 of indomethacin anda steroid. The results in terms of 3-indolyl)-propionate are dispersedtherein. The resulting amounts needed, side effects and increasedphysical activisuspension is subdivided into amber vials with protectionty of the patent are given in the following table:

from light during the subdivision.

TABLE Prior treatment New treatment Side effects Indo- Change in phy-Patient Steroid Amount Duration, methaein, Steroid, Prior Present sicalactivity No. Disease Used (mgJday) yr. (mg/day) Name (mgJday) treatmenttreatment (it any) 1 A 10 100 A 6.5 None. 2 A 10 0.5 200 A 5.0Cushingoid.-- Slight nausea Do. 1 A 10 9.0 200 A 2.5 do one Increased. 1B 0.75 1.0 200 A 2.5 Ulcers 1 C 8 3 150 C 6.0 1 C 8 12.0 150 C 4.0Edema, ulcer,

cushingoid. 1 C 8 12 100 C 6.0 .do do None. 1 O 6 12 200 C do Increased.2 B 0.75 4 200 B Much less wheez- None.

1 B 0 5-0. 75 6 150 B 0. -0. 38 Cushingoid None Increased. 1 B 0 751.5 4150 B 0.375 Edema, Cushingoid do Do. 1 B 0.5 10 150 B 0.05 Do. 1 B 1.0 5400 B 0.5 Rash, edema,

blood dyscrasic. Edema Do. 3 D 8 10 200 A 1 E 1.8 2 125 E D 2 F 4.5 3200 F 1 G 7.5 150 G 1 F 3.0 150 F 1 H 3.0 150 H 1 G 150 G Disease:1Rheumatoid Arthritis; 2-Bronehial Asthma; 3Rheumatoid Spondylitis. Newtreatment (name): APrednisone; BDexamethasone; C-Triameinolone;D6-a-methy1predmsolone; E-Betamethasone; F-Fiuprednisolone;G-Prednisolone; HParamethasone.

EXAMPLE 12 What is claimed is:

1. A pharmaceutical preparation in unit dosage form Per w comprising 25mg. of indomethacin and 0.125 mg. of dex- Dexamethasone 5 amethasone.l-p-chlorobenloyl z-methyl's-methoxy'3'indolyl' 2. A pharmaceuticalpreparation in unit dosage form acetic acid 0.050 comprising 25 mg. ofindomethacin and 0.250 mg. of Sodium carboxymethylcellulose 1.00 40dexamethasone. Polysorbate 80 0.02 References Cited Sodium chloride PBenzyl alcohol 0.90 Pyrogen-free water to make 1.00 ml. 63464 2/1961Australia OTHER REFERENCES The sodium carboxymethylcellulose,polysorbate 80, so- Wiesel et al., The Am. J. of the Medical Services,vol.

dium chloride and benzyl alcohol are dissolved in ap- PP- 415-418(Octobfir proximately 80% of the required volume of pyrogen-free water.The solution is sterilized by filtration through bacl g pteria-resistant candles. Sterile microcrystalline hydro cor- S515 anXammer tisone and 1-p-ch1orobenzoyl-2-methyl-5-methoxy-3-indol- CLyl-acetic acid are added to and dispersed in the sterilized 424 274

